PKMζ-KIBRA interactions, molecular turnover, and memory.

How can the molecules that strengthen synaptic connections maintain memory in the face of molecular turnover? Our previous work showed that persistent interaction between the postsynaptic scaffolding protein, KIBRA, and the autonomously active PKC isoform, PKMζ, is crucial for maintaining synaptic long-term potentiation (LTP) and memory for at least a month. This duration is longer than the lifespans of individual KIBRA and PKMζ molecules. Biophysical modeling of the interaction suggests oligomers of KIBRA-PKMζ dimers, but not individual dimers or monomers, can overcome molecular turnover by continually incorporating newly synthesized KIBRA and PKMζ, replacing those that have degraded. Here we used AlphaFold 3 to predict the structures of KIBRA-PKMζ heterodimers and heterohexamers and to examine the sites of action of two structurally distinct inhibitors of KIBRA-PKMζ interaction that disrupt established late-LTP and long-term memory. The structures predict that the peptide K-ZAP blocks formation of heterodimers, whereas the small molecule ζ-stat prevents PKMζ of one heterodimer from binding a second KIBRA and PKMζ, essential for forming larger oligomeric structures. We show that ζ-stat, like K-ZAP, disrupts 1-month-old spatial memory. Thus, continual formation of KIBRA-PKMζ oligomers can be a core molecular mechanism driving the persistence of long-term memory in the face of molecular turnover.